This invention relates generally to the field of substance extraction and detection from a subject""s body utilizing electrical signals, including substances extracted by iontophoresis.
The transport of various agents such as metabolites, drugs and nutrients across tissues is a function primarily of three factors: tissue permeability, the presence or absence of a driving force and the size of the area through which transport occurs. The lack of inherent permeability of many molecular permeants severely impedes the movement of permeants across a layer of tissue. Permeability in skin is low because the unique, tightly packed arrangement of cells in the membrane and the intercellular lipid matrix make the stratum corneum relatively impermeable, especially to polar and ionized species.
Iontophoresis is one method that has been explored as a way to effectuate transport of agents across a tissue. Such methods have been used primarily to deliver rather than extract agents through a tissue into the body (e.g., transdermal delivery of a drug). Iontophoresis is characterized by the application of an electrical current to enhance transport across a tissue by driving ionized agents through the membranes as a result of a direct electrical field effect (e.g., electrophoresis), electroosmosis, or through electrically induced pore formation (electroporation). In practice, iontophoretic methods generally involve positioning an electrode that includes some type of reservoir on the tissue through which delivery is to occur. The reservoir typically includes a solution or an absorbent pad that contains the substance to be transferred. This is called the active or drug electrode. Another electrode is also placed in contact with the tissue to allow for the completion of the electrical circuit. This is called the return, inactive, or indifferent electrode.
Application of a voltage between the two electrodes and across the tissue generates a current that causes the ionized agent of one charge to move towards the electrode of the opposite charge. In the standard configuration in which iontophoresis is used to deliver an agent, this current drives the agent in the reservoir at the active electrode through the tissue and into the body. Neutral agents can also be transported, albeit less effectively than ionized agents, via electroosmosis. The electric field also induces new pore formation on the tissue and increases its permeability. When the tissue is skin, the agent penetrates the stratum corneum and passes into the dermo-epidermal layer. The outermost portion of the dermis layer is typically referred to as the papillary layer and contains a network of capillaries from the vascular system. This network absorbs the agent and subsequently moves it to the main portion of the vascular system.
During analyte extraction, with the analyte traverses the membrane outward from the dermo-papillary layer to the surface of the stratum corneum under the influence of an electrical field. When iontophoresis is used to extract a substance from a body, the reservoir is the site at which the substance is collected. The current formed between the electrodes acts to extract the substance from the vascular network through the tissue and into the reservoir.
A majority of iontophoretic methods utilize constant-current DC signals to effectuate transport. There are several problems associated with such methods that have resulted in limited acceptance by regulatory authorities, clinicians, and patients. Literature and unpublished data from the inventors"" laboratories suggest that one shortcoming of constant-current DC is the inability to achieve a constant flux at constant current due to time-dependent changes in tissue porosity, accompanying changes in pore surface charge density and effective pore size over the course of treatment. Such changes and the resulting flux variability pose significant problems in effectively controlling the transport (either delivery or extraction) of agents through a tissue by iontophoresis. It is generally known that with constant-current DC methods the transference number (fraction of total current carried by a particular charged species) for the bioactive agent changes with time over the course of a typical iontophoresis procedure. Thus, while application of the DC signal initially results in a state of electroporation, with time the properties of the pores change. This trend can be monitored by the changes in the tissue electrical resistance and/or the changes in the transference number with time during iontophoretic transport. This variability in transference number means that the amount of agent transported across a tissue varies with time and cannot be controlled, monitored, nor predicted effectively. Problems in controlling the extent of electroporation with constant-current DC methods also result in high inter- and intra-patient variability. Hence, not only does the amount of agent transported vary as a function of time, there is further day-to-day variation for the same individual, as well as variation from person to person.
Yet another problem is a function of byproducts formed during iontophoresis. With many direct current systems, transport is accompanied by water hydrolysis that causes significant pH shifts at the electrodes. In particular, protons accumulate at the anode while hydroxide ion accumulates at the cathode. Such pH shifts result in electrochemical bums that can cause tissue damage. In addition, water hydrolysis results in gas formation that interferes with the contact, and hence the electrical conduction, between the electrode components and tissue surface. The use of pure AC ameliorates water hydrolysis and subsequent problems with tissue irritation and gas formation.
Various strategies have been tested to address these problems, including the use of different wave-forms and pulsed DC signals rather than constant-current signals. It has been suggested that the use of pulsed DC signals should theoretically provide improved performance by allowing skin capacitance to discharge, thereby allowing for more controlled current flow and agent transport. However, many DC pulsed methods suffer from at least some of the same general problems as the constant-current DC methods.
The following U.S. patents are illustrative of general pulsed DC methods: U.S. Pat. No. 5,391,195 to Van Groningen; U.S. Pat. No. 4,931,046 to Newman; and U.S. Pat. No. 5,042,975 to Chien et al. Certain DC methods employ a combination of pulsed and continuous electric fields (see, e.g., U.S. Pat. No. 5,968,006 to Hofmann). Each of the foregoing patents, however, are limited in that they discuss only methods for delivering substances across a tissue into the body of an individual. These patents include no discussion of methods for extracting compounds from a body across a tissue. Furthermore, these patents only discuss the use of DC signals to perform iontophoresis; the patents include no discussion on how AC signals can be utilized to effectuate transport. In particular, these patents do not discuss how to maintain a substantially constant electrical state in order to maintain substantially constant levels of transport (e.g., a transference number) for the substance(s) being transported.
The iontophoretic literature on balance has taught against the utility of AC signals in conducting iontophoresis. It has been the belief of many of those skilled in the art that an AC signal lacks the necessary driving force to achieve effective iontophoretic transport; instead, the view has been that the driving force of an applied DC signal is required to transport a charged species. The bidirectional nature of an AC signal, led many to conclude that the use of an AC signal would result in inefficient transport at best, and perhaps no net transfer at all. For example, in U.S. Pat. No. 5,391,195 it is noted that xe2x80x9cthe negative pulse [of an alternating current] would result in an inverse effect to the positive pulse, thereby reducing the efficiency of treatment.xe2x80x9d
Nonetheless, certain investigators have discussed the use of AC signals for specific purposes in conducting iontophoresis. For example, several patents to Sabalis (see, e.g., U.S. Pat. Nos. 5,312,325; 5,328,454; 5,336,168; and 5,372,579) discuss systems in which a current oscillator is utilized to apply periodic electrical variations to the skin of a patient, the goal being to trigger rhythmical variations of the potential and resistance of the skin that reinforce the natural delivery rhythms of the individual being treated. Some discuss the use of AC signals as a way to more efficiently deliver multiple substances (e.g., a drug and a substance that inhibits blood clot formation) having opposite charges (see, e.g., U.S. Pat. No. 5,328,453). Others have discussed methods that involve application of a series of separate or overlapping waveforms that can include an AC component (see, e.g., U.S. Pat. Nos. 5,135,478 and 5,328,452 to Sabalis, and U.S. Pat. No. 5,421,817 to Liss et al). Liss et al., however, reinforced the view that the use of an AC signal is not preferred, noting that a reversal in polarity will xe2x80x9ctend to reverse or slow the transdermal delivery of the drug.xe2x80x9d
There has also been some discussion in the literature regarding the use of AC signals in iontophoresis to minimize the electrochemical burns that can occur with DC methods (see, e.g., Howard et al., (1995) Arch. Phys. Med. Rehabil. 76:463-466; and U.S. Pat. No. 5,224,927 to Tapper). The use of AC signals to control and reduce skin irritation after passive or iontophoretic transport of a drug has also been discussed (see, e.g., Okabe et. al., Journal of Controlled Release, Volume 4, Year 1986, pages 79-85), as has the use of AC signals in related methods such as in the treatment of hyperhidrosis (see, e.g., Reinauer, et al. (1993) Br. J. Derm. 129:166-169). Some researchers (see, e.g., U.S. Pat. No. 6,018,679 to Dinh) have examined the use of a brief current reversal as a means of withdrawing potentially irritating compounds from the tissue following their iontophoretic delivery.
However, none of these patents or articles discuss the issue or problems of extracting substances from a body across a tissue. Instead, these patents and publications focus on delivery of an agent into the body of an individual. Additionally, none of these patents or publications discuss the use of an AC signal to maintain a substantially constant electrical state to control extraction in a predictable fashion.
A limited number of patents discuss certain methods of using iontophoresis in extraction of a substance from the body of an individual across a tissue. U.S. Pat. No. 5,019,034 to Weaver et al. discusses methods that utilize a series of short DC pulses to induce electroporation, in particular a state referred to as reversible electrical breakdown. Various forces can then be utilized to effectuate extraction of a substance across a tissue. Once electroporation is established, the nature of the DC pulses (e.g., pulse duration, shape and frequency) is maintained until transfer is complete. U.S. Pat. Nos. 5,730,714 and 5,362,307 to Guy et al. and U.S. Pat. No. 5,279,543 to Glikfeld et al. discuss methods for extracting and delivering substances by iontophoresis utilizing an apparatus characterized by a particular electrode arrangement. U.S. Pat. Nos. 5,771,890 and 6,023,629 to Tamada discuss particular methods in which the direction of a direct current is periodically reversed during sampling of a substance. The frequency of current reversal discussed in the ""890 and ""629 patents is typically very low, tending to fall within the range of 1 cycle per 20 seconds to about 1 cycle per 4 hours. The methods discussed by Guy et al. and Glikfeld et al. are limited to DC methods and Weaver et al. discuss only DC pulse methods. As with all the foregoing patents and publications, Weaver et al., Guy et al., Glikfeld et al. nor Tamada discuss the use of an AC signal to maintain a substantially constant electrical state.
Thus, none of the foregoing patents and articles address the challenge of maintaining a substantially constant electrical state and a substantially constant electroporative state such that transport of a substance across the tissue, and particularly extraction of a substance, occurs in a predictable and controlled fashion during the time period for transport. Nor is there a discussion of methods for reducing intra- and inter-subject variability that plagues many iontophoretic methods.
Methods for extracting different substances across a tissue utilizing an AC signal are provided. The methods can be utilized to extract a number of different substances such as endogenous substances located within the body of an individual, pharmaceutical substances, markers of disease and metabolites. During the extraction process, the AC signal is used to maintain a substantially constant electrical state in a region of the tissue through which extraction occurs, thereby allowing substances to be transported across the tissue in a controlled and predictable manner. The methods have utility in a wide range of applications. For example, certain methods can be utilized in various therapeutic treatments to monitor the level of a metabolite or pharmaceutical agent. Other methods can be utilized in diagnostic applications to detect the presence of a disease marker, for instance.
Thus, certain methods more specifically involve extracting a substance from a body through a tissue by supplying one or more electrical signals, one of which is an AC signal that is applied to the tissue. The AC signal is then adjusted so as to maintain a substantially constant electrical state within a region of the tissue, wherein maintenance of the substantially constant electrical state facilitates extraction of the substance. The AC signal is typically adjusted to maintain a substantially constant state of electroporation in the region of the tissue throughout the time period in which the substance is extracted. With some methods, the electrical state that is maintained by the AC signal is an electrical conductance or electrical resistance. The AC signal applied to the tissue can have essentially any waveform. The waveform can be symmetric or asymmetric, thus including square, sinusoidal, saw-tooth, triangular and trapezoidal shapes, for example. The frequency of the AC signal tends to be at least about 1 Hz, although in other instances the frequency is within the range of about 1 Hz to about 1 kHz, or about 1 kHz to about 30 kHz.
Other extraction methods include an optional electrical prepulse applied to the tissue prior to the AC signal to induce electroporation within the region of the tissue through which extraction is to occur. The prepulse can be either an AC signal or a DC signal. The voltage of the prepulse generally is in the range of about 1 to about 90 V, in other instances about 5 to about 20 V, in still other instances about 20 to about 40 V, and in yet other instances about 40 to about 90 V. The actual voltage can be any particular voltage or span of voltages within these ranges.
Extraction of the substance across the tissue can be via passive diffusion through an electroporated region induced by the AC signal. Certain methods, however, utilize an optional DC offset signal that is applied to the tissue in combination with the AC signal. The DC offset signal is effective to promote extraction of the substance through the region maintained at a substantially constant electrical state. The DC offset signal is typically applied substantially continuously during extraction of the substance and is of a voltage or current, effective to control the rate of extraction. The DC offset signal is usually in the range of about 0.1 to 5 V and about 0.01 to 0.5 mA/cm2, but can include any particular voltage, current or span of voltages or currents within this range. In certain methods, the DC offset signal is applied utilizing two electrodes in contact with the tissue and the direction of current flow of the DC offset signal is periodically reversed between the two electrodes.
Still other methods combine both the prepulse and the DC offset with the AC signal to extract substances across a tissue. Such methods generally involve applying the electrical prepulse to the tissue prior to the AC signal to induce electroporation within the region. The DC offset signal is also applied to the tissue and is effective to promote extraction of the substance through the region maintained at a substantially constant electrical state by the AC signal.
The methods can be utilized with a variety of different types of tissue, including both animal and plant tissues. The tissues can be part of a body surface or can be artificial in nature. Usually the tissue is skin or mucosal tissue, particularly human skin or mucosal tissue. A variety of substances can also be extracted, including charged and uncharged substances.